PT97882B - PREPARATION PROCESS OF NEW 2-PIPERAZINYL BENZIMIDAZOLE DERIVATIVES - Google Patents
PREPARATION PROCESS OF NEW 2-PIPERAZINYL BENZIMIDAZOLE DERIVATIVES Download PDFInfo
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- PT97882B PT97882B PT97882A PT9788291A PT97882B PT 97882 B PT97882 B PT 97882B PT 97882 A PT97882 A PT 97882A PT 9788291 A PT9788291 A PT 9788291A PT 97882 B PT97882 B PT 97882B
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- benzimidazole
- group
- piperazinyl
- hydrogen atom
- diphenylmethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Animal Behavior & Ethology (AREA)
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- Hospice & Palliative Care (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
PATENTE DE INVENÇÃOINVENTION PATENT
DEIN
PROCESSO DE PREPARAÇÃO DE NOVOS DERIVADOS DE 2-PIPERAZINILBENZIMIDAZOLPREPARATION PROCESS FOR NEW 2-PIPERAZINYL BENZIMIDAZOL DERIVATIVES
REQUERENTEAPPLICANT
FABRICA ESPAROLA DE PRODUCTOS QUÍMICOS Y FARMACÊUTICOS, SA (FAES)FABRICA ESPAROLA DE PRODUCTOS QUÍMICOS Y FARMACÊUTICOS, SA (FAES)
INVENTORESINVENTORS
AURÉLIO ORJALES-VENEROAURÉLIO ORJALES-VENERO
ROSA RODES-SOLANES *****************************************************************************ROSA RODES-SOLANES ********************************************** *******************************
O presente invento refere-se a uma serie de novos derivados de 2-piperazinilbenzimidazol de formula (I) e seus sais de adição com ácidos farmaceuticamente aceitáveis, descrevendo-se o método de preparação dos mesmos.The present invention relates to a series of new 2-piperazinylbenzimidazole derivatives of formula (I) and their addition salts with pharmaceutically acceptable acids, describing the method of preparing them.
Na formula (I) Re um átomo de hidrogénio, um grupo alquilo de cadeia curta, ou um radical fenilo, substituido ou não por um alogéneo na posição 4, e Rj é um ãtomo de hidrogénio, um radical alcoxicarbonilo de cadeia curta, um grupo hidroximeti lo ou um grupo difenilmetilo. 0 grupo alquilo de cadeia curta e um radical carbonado de uma a três unidades de carbono, tanto linear como ramificado; o grupo alcoxilo de cadeia curta ”e um resto 0R£ em que R£ tem o mesmo significado atribui do previamente a um grupo alquilo de cadeia curta; um halogeneo é fluor, cloro, bromo ou iodo. Também ficam compreendidos no presente invento os sais de adição destes compostos com ãcidos inorgânicos, tais como clorídrico, bromidríco, fosfórico e sulfurico, assim como com ãcidos orgânicos, tais como acético, fumãrico, tartarico, oxãlico e benzoico.In formula (I) Re a hydrogen atom, a lower alkyl group, or a phenyl radical, whether or not substituted by an halogen in position 4, and Rj is a hydrogen atom, a short chain alkoxycarbonyl radical, a group hydroxymethyl or a diphenylmethyl group. The lower alkyl group and a carbon radical of one to three carbon units, both linear and branched; the lower alkoxy group ”and a remainder 0 R £ where R £ has the same meaning as previously assigned to a lower alkyl group; a halogen is fluorine, chlorine, bromine or iodine. Also included in the present invention are the addition salts of these compounds with inorganic acids, such as hydrochloric, hydrobromic, phosphoric and sulfuric, as well as with organic acids, such as acetic, fumaric, tartaric, oxalic and benzoic.
= 2 == 2 =
processo de preparação dos compostos mencionados consiste basicamente em fazer reagir um derivado halogenado de formula geralThe preparation process for the mentioned compounds basically consists of reacting a halogenated derivative of the general formula
CHgR em que R pode ser hidrogénio, um grupo alquilo de cadeia curta e um radical fenilo, substituido ou não na posição quatro por um halogéneo, e X Ó um halogéneo, de preferência cloro, com um derivado da piperazina, de formula geral /“ΛCHgR where R can be hydrogen, a lower alkyl group and a phenyl radical, whether or not substituted in position four by a halogen, and X Ó a halogen, preferably chlorine, with a piperazine derivative, of the general formula / “ Λ
H-N N-R \_y em que Rj pode ser um átomo de hidrogénio, um radical alcoxicarhonilo e um grupo difenilmetilo.H-N N-R \ _y where Rj can be a hydrogen atom, an alkoxycarbonyl radical and a diphenylmethyl group.
A reacção realiza-se misturando quantidades equimoleculares dos reagentes (II) e (III), admitindo-se um excesso da piperazina (III), que pode chegar a ser de 5 a 1 relativamente ao derivado halogenado (II), e aquecendo a mistura de reacção entre 80 e 150QC durante um espaço de tempo compreendido entre cinco e trina minutos.The reaction is carried out by mixing equimolecular quantities of reagents (II) and (III), admitting an excess of piperazine (III), which can reach 5 to 1 in relation to the halogenated derivative (II), and heating the mixture between 80 and 150 ° C for a period of between five and three minutes.
Os derivados halogenados (II) e as piperazinas (III), utilizadas na reacção são produtos, conhecidos e podem ser preparados por métodos convencionais.Halogenated derivatives (II) and piperazines (III) used in the reaction are known products and can be prepared by conventional methods.
As actívidades farmacológicas dos compostos referidos no presente invento foram postas a prova mediando experiências com animais utilizando processos farmacológicos bem estabelecidos. A titulo de exemplo citam-se duas das realizadasThe pharmacological activities of the compounds referred to in the present invention were tested by mediating animal experiments using well-established pharmacological processes. As an example, two of those carried out
a) Ratas Wistar de ambos os sexos, de 180-220g de peso, foram anestesiadas com uretano (1,25 g/Kg. i.p.), posteriorrnente submetidas a canulação de tra= 3 =a) Wistar rats of both sexes, weighing 180-220 g, were anesthetized with urethane (1.25 g / kg. i.p.), subsequently subjected to tra = 3 =
queia, artéria carotida e veia jugular, com respiração expontânea e a 37-382C de temperatura rectal. Uma vez estabelizados os parâmetros de pressão arterial (PA) e frequência cardíaca (FC), induziu-se o reflexo de Bezold-Jarisch por injecçâo intravenosa rápida de 80 pg/kg do complexo serotonina-creatinina sulfato. Dez minutos depois e apos recuperação de FC e PA a níveis constantes, injectaram-se i.v. os produtos aqui reivindicados e, a seguir a um período de cinco minutos, repetiu-se a injecçâo i.v. do complexo serotonina-creatinina sulfato, quantificando a inibição do reflexo de Bezold-Jarisch. Todos os compostos ensaiados mostraram actividade quando foram administrados iv na extensão compreendida entre 0,3 e 10 pg/kg, manifestando-se, portanto, como antagonistas dos receptores 5HT3 da serotonina.queia, carotid artery and jugular vein, with spontaneous breathing and at 37-382C rectal temperature. Once the blood pressure (BP) and heart rate (HR) parameters were established, the Bezold-Jarisch reflex was induced by rapid intravenous injection of 80 pg / kg of the serotonin-creatinine sulfate complex. Ten minutes later and after recovery of HR and PA at constant levels, the products claimed here were injected iv and, after a period of five minutes, the iv injection of the serotonin-creatinine sulfate complex was repeated, quantifying the inhibition of Bezold-Jarisch reflex. All tested compounds showed activity when iv was administered between 0.3 and 10 pg / kg, thus manifesting themselves as serotonin 5HT3 receptor antagonists.
b) Estudou-se a inibição do vomito induzido por cisplatino em cão consciente. Os produtos administraram-se por via endovenosa, 30 minutos antes e 2 horas depois do cisplatino (3 mg/kg i.v., 1 ml/kg). Contabilizou-se 0 numero de episódios eméticos ocorridos durante cinco horas a partir da administração do cisplatino.b) The inhibition of cisplatin-induced vomiting in a conscious dog was studied. The products were administered intravenously, 30 minutes before and 2 hours after cisplatin (3 mg / kg i.v., 1 ml / kg). The number of emetic episodes that occurred during five hours from the administration of cisplatin was counted.
Os produtos do presente invento foram mais activos que a metocloramida na prevenção do vomito induzido por cisplatino.The products of the present invention were more active than metochloramide in preventing cisplatin-induced vomiting.
Os resultados destes ensaios demonstram que os compostos do invento antagonizam a acção da serotonina a nível dos receptores 5HT3 e, por conseguinte, estão indicados na prevenção do vomito induzido por agentes anticancerosos, tais como 0 cisplatino e as radiações, e são potencialmente úteis na profilaxia e tratamento da enxaqueca, ansiedade e outros transtornos neurãlgicos.The results of these tests demonstrate that the compounds of the invention antagonize the action of serotonin at the level of 5HT3 receptors and, therefore, are indicated in the prevention of vomiting induced by anti-cancer agents, such as cisplatin and radiation, and are potentially useful in prophylaxis. and treatment of migraine, anxiety and other neurological disorders.
Os seguintes exemplos oferecem mais pormenores sobre 0 invento sem que este fique limitado de modo algum aos mesmos.The following examples offer more details about the invention without being limited in any way to them.
Exemplo 1Example 1
Preparação de l-metil-2-(l-piperazinil)-lH-benzimidazo1Preparation of l-methyl-2- (l-piperazinyl) -1H-benzimidazo1
Uma mistura de 5g (30 mmol) de 2-cloro -1-meti 1-lH-benzimidazol e 12,9 g (150 mmol) de piperazina anidra e aquecida a 125Q C durante 15 mi nu = 4 =A mixture of 5g (30mmol) of 2-chloro-1-methyl 1-1H-benzimidazole and 12.9g (150mmol) of anhydrous piperazine and heated at 125 ° C for 15 ml = 4 =
Ιη.Ιη.
tos. Sobre a mistura de reacção juntam-se 50 ml. de dissolução aquosa de NaOH 10% e extrai-se com diclorometano (3 x 20 ml). Os extractos orgânicos reunidos secam-se sobre sulfato de sódio anidro. Depois de destilar o dissolvente no vacuo, obtem-se um óleo que, ao ser tratado com Óter, proporciona 4,5 g (69% rendimento) de um solido branco caracterizado como 1-meti1-2-(1-piperazini1)-lH-benzimidazol, cujo ponto de fusão Ó 80-22 C.tos. 50 ml are added to the reaction mixture. aqueous 10% NaOH and extracted with dichloromethane (3 x 20 ml). The combined organic extracts are dried over anhydrous sodium sulfate. After distilling the solvent in the vacuum, an oil is obtained which, when treated with Oter, provides 4.5 g (69% yield) of a white solid characterized as 1-meti1-2- (1-piperazini1) -lH -benzimidazole, whose melting point is 80-22 C.
De forma análoga preparam-se:Similarly, they prepare:
- 1-FeniImeti1-1-(1-pi perazi ni1)-lH-benzimi dazol.- 1-FeniImeti1-1- (1-pi perazi ni1) -1H-benzimidazole.
PF: 125-7° C.PF: 125-7 ° C.
- l-(4-Fluorofenilmetil)-2-(l-piperazinil)-lH-benzimidazol.- 1- (4-Fluorophenylmethyl) -2- (1-piperazinyl) -1H-benzimidazole.
PF: 84-6° C.MP: 84-6 ° C.
- 1-Eti1-2-(1-piperazini1)-lH-benzimidazol. PF (fumarato): 170-2° C.- 1-Eti1-2- (1-piperazini1) -1H-benzimidazole. PF (fumarate): 170-2 ° C.
- 1-Propi1-2-(1-piperazini1)-lH-benzimidazol. PF (fumarato): 175-7° C.- 1-Propi1-2- (1-piperazini1) -1H-benzimidazole. PF (fumarate): 175-7 ° C.
Exemplo 2Example 2
Preparação de l-metil-2[(4-etoxicarbonil )-l-piperazinil]-lH-benzimidazolPreparation of 1-methyl-2 [(4-ethoxycarbonyl) -1-piperazinyl] -1H-benzimidazole
Aquece-se durante 25 minutos a 120° C. uma mistura de 3,3 g (20 mmol) de 2-cloro-l-metil-lH-benzimidazol e 3,2 g (20 mmol) de l-etoxicarbonilpiperazina Sobre a mistura de reacção juntam-se 40 ml de solução aquosa de NaOH a 10% e extrai-se com diclorometano (3 x 20 ml). Os extractos orgânicos reunem-se, secam-se com sulfato sÓdico anidro e elimina-se o dissolvente a pressão reduzida. Obtem-se 4,8 g (84% rendimento) do produto como um sólido branco que se purifica por cromatografia de coluna, empregando como eluente diclorometano/metanol (95/5). PF: 122-42 C.A mixture of 3.3 g (20 mmol) of 2-chloro-1-methyl-1H-benzimidazole and 3.2 g (20 mmol) of 1-ethoxycarbonylpiperazine is heated for 25 minutes at 120 ° C. To the reaction, 40 ml of 10% aqueous NaOH solution are added and extracted with dichloromethane (3 x 20 ml). The organic extracts are combined, dried with anhydrous sodium sulfate and the solvent is removed under reduced pressure. 4.8 g (84% yield) of the product are obtained as a white solid which is purified by column chromatography, using dichloromethane / methanol (95/5) as eluant. PF: 122-42 C.
De forma anamoga preparam-se:In anamoga form they are prepared:
- 1-metil-2-[(4-difenilmeti 1)-1-piperazinil]-lH-benzimidazol.- 1-methyl-2 - [(4-diphenylmethyl 1) -1-piperazinyl] -1H-benzimidazole.
PF (fumarato): 123-52 C = 5 = ΐη,PF (fumarate): 123-52 C = 5 = ΐη,
- 1-Fenilmeti1-2-Ε(4-di -fenilmetii)-1-pi perazi ni1j-lH-benzimi dazol.- 1-Phenylmethyl1-2-Ε (4-di-phenylmethyl) -1-pi perazi ni1j-1H-benzimidazole.
PF (fumarato): 155-82 C.PF (fumarate): 155-82 C.
Exemplo 3Example 3
Preparação de l-metil-2-[(hidroximetil)-l-piperazini1]-lH-benzimidazolPreparation of l-methyl-2 - [(hydroxymethyl) -l-piperazini1] -lH-benzimidazole
Suspendem-se 0,5 g de hidreto de 1itio e aluminio em 75 ml de eter seco. Adicionam-se lentamente 4,3 g (15 mmol) de l-metil-2-[(4-etoxicarbonil)-l-piperazinil]-lH-benzimidazol, mantendo a agitação durante dez horas ã temperatura ambiente. Hidraliza-se com 20 ml de ãgua e 10 ml de dissolução aquosa de NaOH a 10%. Separam-se os hidróxidos alcalinos precipitados por filtração e o filtrado extrai-se com 3 x 20 ml de diclorometano. Os extraetos orgânicos secam-se com sulfato sódico anidro e o dissolvente elimina-se no vacuo. Ficam 3,4 g de um Óleo que se purifica por cromatografia de coluna, empregando como eluente diclorometano/metanol (9/1), obtendo-se 1,8 g (50% rendimento) do produto do titulo. PF: 82-52 C.0.5 g of aluminum hydride and aluminum are suspended in 75 ml of dry ether. 4.3 g (15 mmol) of 1-methyl-2 - [(4-ethoxycarbonyl) -1-piperazinyl] -1H-benzimidazole are added slowly, maintaining stirring for ten hours at room temperature. Hydralize with 20 ml of water and 10 ml of 10% aqueous NaOH dissolution. The precipitated alkali hydroxides are filtered off and the filtrate is extracted with 3 x 20 ml of dichloromethane. The organic extracts are dried with anhydrous sodium sulfate and the solvent is removed in a vacuum. 3.4 g of an oil are left and purified by column chromatography, using dichloromethane / methanol (9/1) as eluent, obtaining 1.8 g (50% yield) of the title product. PF: 82-52 C.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES9101147A ES2038532B1 (en) | 1991-05-10 | 1991-05-10 | PROCEDURE FOR THE PREPARATION OF NEW DERIVATIVES OF 2-PIPERACINILBECIMIDAZOLE. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PT97882A PT97882A (en) | 1993-04-30 |
| PT97882B true PT97882B (en) | 1998-10-30 |
Family
ID=8272328
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT97882A PT97882B (en) | 1991-05-10 | 1991-06-06 | PREPARATION PROCESS OF NEW 2-PIPERAZINYL BENZIMIDAZOLE DERIVATIVES |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0512939B1 (en) |
| JP (1) | JPH072795A (en) |
| KR (1) | KR100227458B1 (en) |
| AT (1) | ATE183741T1 (en) |
| AU (1) | AU666477B2 (en) |
| CA (1) | CA2068292A1 (en) |
| DE (1) | DE69229845T2 (en) |
| DK (1) | DK0512939T3 (en) |
| ES (1) | ES2038532B1 (en) |
| GR (1) | GR3031930T3 (en) |
| MX (1) | MX9202178A (en) |
| PT (1) | PT97882B (en) |
| TW (1) | TW200478B (en) |
| ZA (1) | ZA923319B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201744B (en) * | 1991-07-02 | 1993-03-11 | Kanebou Textile Co Ltd | |
| JP3193560B2 (en) * | 1993-04-16 | 2001-07-30 | 明治製菓株式会社 | New benzoxazole derivatives |
| ES2072193B1 (en) * | 1993-05-21 | 1996-02-16 | Espanola Prod Quimicos | NEW DERIVATIVES OF 1-Phenylmethyl Benzimidazole PIPERACINES. |
| FR2731707B1 (en) * | 1995-03-13 | 1997-04-30 | Synthelabo | BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| JP3520177B2 (en) * | 1996-05-09 | 2004-04-19 | 明治製菓株式会社 | Serotonin 5-HT3 receptor partial activator |
| WO2008090200A2 (en) * | 2007-01-25 | 2008-07-31 | Janssen Pharmaceutica Nv | 2- piperazin-1-yl-3h-imidazo[4,5-b]pyridine derivatives |
| EP3347011A4 (en) | 2015-09-11 | 2019-06-19 | Chase Pharmaceuticals Corporation | Muscarinic combination and its use for combating hypocholinergic disorders of the central nervous system |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4351832A (en) * | 1980-04-18 | 1982-09-28 | American Home Products Corporation | 2-(Piperazinyl)-4-pyrimidinamines |
| JPS5879983A (en) * | 1981-11-06 | 1983-05-13 | Kanebo Ltd | Novel benzimidazole derivative, its preparation and pharmaceutical composition thereof |
| US4634704A (en) * | 1983-10-06 | 1987-01-06 | Janssen Pharmaceutica, N.V. | Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines |
| WO1991018904A1 (en) * | 1990-05-30 | 1991-12-12 | American Home Products Corporation | Substituted arylsulfonamides and benzamides |
-
1991
- 1991-05-10 ES ES9101147A patent/ES2038532B1/en not_active Expired - Fee Related
- 1991-06-06 PT PT97882A patent/PT97882B/en not_active IP Right Cessation
-
1992
- 1992-05-01 AU AU15970/92A patent/AU666477B2/en not_active Ceased
- 1992-05-07 ZA ZA923319A patent/ZA923319B/en unknown
- 1992-05-07 KR KR1019920007702A patent/KR100227458B1/en not_active IP Right Cessation
- 1992-05-08 DE DE69229845T patent/DE69229845T2/en not_active Expired - Fee Related
- 1992-05-08 EP EP92500056A patent/EP0512939B1/en not_active Expired - Lifetime
- 1992-05-08 AT AT92500056T patent/ATE183741T1/en not_active IP Right Cessation
- 1992-05-08 DK DK92500056T patent/DK0512939T3/en active
- 1992-05-08 CA CA002068292A patent/CA2068292A1/en not_active Abandoned
- 1992-05-11 MX MX9202178A patent/MX9202178A/en not_active IP Right Cessation
- 1992-05-11 JP JP4144877A patent/JPH072795A/en active Pending
- 1992-05-27 TW TW081104137A patent/TW200478B/zh active
-
1999
- 1999-11-24 GR GR990403022T patent/GR3031930T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9202178A (en) | 1992-11-01 |
| ZA923319B (en) | 1994-02-07 |
| ATE183741T1 (en) | 1999-09-15 |
| DE69229845T2 (en) | 2000-04-27 |
| AU666477B2 (en) | 1996-02-15 |
| ES2038532A1 (en) | 1993-07-16 |
| DK0512939T3 (en) | 2000-03-13 |
| KR100227458B1 (en) | 1999-11-01 |
| EP0512939B1 (en) | 1999-08-25 |
| CA2068292A1 (en) | 1992-11-11 |
| TW200478B (en) | 1993-02-21 |
| JPH072795A (en) | 1995-01-06 |
| PT97882A (en) | 1993-04-30 |
| ES2038532B1 (en) | 1994-02-16 |
| EP0512939A1 (en) | 1992-11-11 |
| GR3031930T3 (en) | 2000-03-31 |
| KR920021527A (en) | 1992-12-18 |
| AU1597092A (en) | 1992-11-12 |
| DE69229845D1 (en) | 1999-09-30 |
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